Asymmetric addition of an electrophile to naphthalenes promoted and stereodirected by alcohol

Article abstract of DOI:10.1021/ja0029477

4-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) reacts with 1-methoxy-4-methylnaphthalene to give the 1,4-addition product in the presence of methanol; the reaction does not proceed in the absence of the alcohol. Methoxy exchange (with CD₃OD) was al

Full text of DOI:10.1021/ja0029477

2946
J. Am. Chem. Soc. 2001, 123, 2946-2957
Asymmetric Addition of an Electrophile to Naphthalenes Promoted
and Stereodirected by Alcohol
Morifumi Fujita,*,† Hironori Matsushima, Takashi Sugimura,* Akira Tai, and
Tadashi Okuyama
Contribution from the Faculty of Science, Himeji Institute of Technology,
Kouto, Kamigori, Ako-gun, Hyogo 678-1297, Japan
ReceiVed August 7, 2000
Abstract: 4-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) reacts with 1-methoxy-4-methylnaphthalene to give the
1,4-addition product in the presence of methanol; the reaction does not proceed in the absence of the alcohol.
Methoxy exchange (with CD3OD) was also observed during the reaction. Reactions of PTAD with 1-(3-
hydroxypropoxy)-4-methylnaphthalene and related naphthalenes afford stereoselectively 1,4-adducts (70-
98% of the major diastereomer). The stereoface-selective addition of PTAD at C-4 with concurrent formation
of an acetal at C-1 takes place in a syn manner, which is induced by the hydrogen-bonding interaction between
PTAD and the hydroxy group. The R-methyl substitution on the propoxy side chain strongly enhances the
stereodifferentiation (90% de) and accelerates the cyclization by the Thorpe-Ingold effect. The alkoxy moiety
of the adduct is easily removed to give 4-methyl-4-amino-4H-naphthalen-1-one with high enantiomeric excess.
The γ-methyl group of the side chain also affects the stereodifferentiation. Thus, the two stereogenic centers
of the (1S,3R)-3-hydroxy-1-methylbutoxy side chain work together to achieve the high stereodifferentiating
1,4-addition from the Si-Re face (up to 96% ee). Epimerization of the cyclic acetal of a minor adduct was
observed during the reaction of 1-(3-hydroxybutoxy)-4-methylnaphthalene, indicating that the minor component
of the final products is derived from the initial minor syn adduct formed from the opposite face. The syn
selectivity of the addition is achieved completely in the initial stage of formation of both the major and the
minor adducts.
Introduction
an external source or more efficiently as an intramolecular
functional group. Many synthetic systems successfully employ
a hydroxy function to promote a reaction and to achieve high
stereoselectivity, but most examples utilize only one of the two
capabilities of alcohol.
Hydrogen-bonding interactions play quite important roles in
various chemical and biochemical phenomena such as molecular
recognition, construction of supramolecular systems, control of
chemo-, regio-, and stereoselectivities of chemical reactions, and
stabilization of transition states and reaction intermediates.1-4
An alcohol function contributes to the selectivity, and the
promotion of a reaction is not only due to its hydrogen-bond
donor ability5-7 but also to its nucleophilic (hydrogen-bond
acceptor) ability.8-12 The alcohol function may be provided by
Asymmetric addition of electrophiles to arenes is still limited13
in comparison with that to olefins8,9,14,15 despite the synthetic
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† E-mail: fuji@sci.himeji-tech.ac.jp.
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10.1021/ja0029477 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/08/2001

Asymmetric Addition of Electrophile to Naphthalenes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2947
and biochemical importance of the resulting products.16-20 Even
nonstereocontrolled additions of electrophiles to arenes have
limitations due to the facile ensuing eliminations which result
in re-aromatization. Nucleophilic trapping24 of a cationic
intermediate25 is necessary to complete a successful electrophilic
addition to arenes (Scheme 1), but a direct mutual reaction of
the electrophile and the nucleophile must be avoided.
Scheme 1
Adam and co-workers6 found that reaction of singlet oxygen
with a hydroxymethylnaphthalene gave stereoselectively an
unstable endoperoxide and showed that hydrogen-bonding
interactions of the alcohol function play an important role in
stereoselective additions to the arene.
In the present paper, we report that an alcohol function
promotes the electrophilic reaction of 4-phenyl-1,2,4-triazoline-
3,5-dione (PTAD)5,15,26-32 with 4-substituted 1-alkoxynaphtha-
lenes to give stereospecifically syn addition products. Introduc-
tion of the (1S,3R)-3-hydroxy-1-methylbutoxy group to the
naphthalene affords an optically active adduct as a stable
product. The chiral auxiliary is easily removed from the adduct
to give 4-substituted 4-amino-4H-naphthalen-1-one in a high
enantiomeric excess. Both the hydrogen-bonding and nucleo-
philic abilities of the alcohol function are involved in this
asymmetric addition. The novel role of the alcohol function in
this electrophilic addition to arenes is revealed by a stereo-
chemical analysis of the reaction.
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eosmium(II) arene complexes has been reported: (a) Chordia, M. D.;
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Results
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1998, 501-506. (b) Adam, W.; Gu¨thlein, M.; Peters, E.-M.; Peters, K.;
Wirth, T. J. Am. Chem. Soc. 1998, 120, 4091-4093.
Reactions of PTAD with a series of 1-alkoxynaphthalenes,
1-7, were examined, focusing attention on their stereochem-
istry. The enantiomerically pure side chain of the substrates 4-7
can easily be introduced by the Mitsunobu reaction.33
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the Presence of Methanol. The 1H NMR spectrum of a mixture
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2948 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Fujita et al.
Scheme 2
Scheme 3
Figure 1. Reaction of 1 (80 mM) with PTAD (275 mM) in the presence
of CD3OD (1.0 M) in CDCl3 at 293 K, monitored by 1H NMR: 1 (O),
2 (b), 9 (4), 10 (2), and CH3OD (0).
Table 1. Time Dependence of the Diastereomeric Ratio of the
Adduct 9 and Yield of Adducts 9 and 10 in the Electrophilic
Addition of PTAD (275 mM) to 1 (80 mM) in the Presence of
CD3OD (1.0 M) in CDCl3
9
10
of 1-methoxy-4-methylnaphthalene (1) (0.32 M) and PTAD
(0.39 M) in CDCl3 solution did not change during 8 h at 298 K
in the dark.27,28 When CH3OH (1.6 equiv) was added to the
mixture, immediate formation of adduct 8 was detected (Scheme
2) while most of the substrate 1 still remained (35% conversion).
However, the adduct 8 disappeared in 1 h at 293 K in the dark
with accompanying decomposition of PTAD32 but the unreacted
substrate 1 remained. When CD3OD was employed, a signal
due to methanol (3.4 ppm) developed with concomitant decrease
of the signal of the methoxy group of 1 (3.96 ppm). The
formation of adduct 9 was also observed in addition to the
methanol exchange (Scheme 3). Furthermore, formation of the
bis(deuteriomethoxy)adduct 10 was also indicated by the loss
of the methoxy signal compared with the intensity of the
4-methyl signal.
time (min)
a:ba
yield (%)
yield (%)
5
9
14
19
25
33
43
>95:5
84:16
80:20
72:28
69:31
61:39
59:41
35
32
25
18
15
9
8
22
30
33
33
35
30
7
a Relative peak areas at δ ) 3.14 (a) and 3.13 (b) ppm due to the
diastereomers.
Time-dependent changes of the substrate and the products
are shown in Figure 1. The time course of the reaction suggests
that methoxy exchange of 1 occurs with concurrent decomposi-
tion of adduct 9. It is noteworthy that two singlet signals
(δ ) 3.14 (a) and 3.13 ppm (b)) due to the methoxy group of
9 were observed and the relative peak areas change with the
progress of reaction as shown in Table 1. Although the
configuration of 9 could not be determined because of its
instability, the two signals must correspond to the cis and trans
1
isomers. This was confirmed by comparison of the H NMR
spectrum of mixture 9 with that of the epimeric mixutre 11,
which was obtained by reaction of the deuterated substrate 2
with PTAD in the presence of CH3OH (Scheme 4). The
chemical shift of the major peak due to the methoxy group of
9 (3.14 ppm) is different from that of 11 (3.13 ppm) as shown
in Figure 2.
Figure 2. 1H NMR spectra of reaction mixtures of (a) 1 (80 mM) +
CD3OD (1.0 M) + PTAD (275 mM) in CDCl3 at 19 min and (b) 2
(128 mM) + CH3OH (254 mM) + PTAD (185 mM) in CDCl3 at 6
min. Assignments of the signals are shown in the spectra.
Reactions of Hydroxyalkoxynaphthalenes. When 1-(3-
hydroxypropoxy)-4-methylnaphthalene (3) was employed for
(32) Decomposition of PTAD by alcohol has been reported: (a) Mackay,
D.; Taylor, N. J.; Wigle, I. D. J. Org. Chem. 1987, 52, 1288-1290. (b)
Borhani, D. W.; Greene, F. D. J. Org. Chem. 1986, 51, 1563-1570. (c)
Izydore, R. A.; Johnson, H. E.; Horton, R. T. J. Org. Chem. 1985, 50,
4589-4595. (d) Nachbaur, E.; Faleschini, G.; Belaj, F.; Janoschek, R.
Angew. Chem. Int. Ed. Engl. 1988, 27, 701-703.
(33) (a) Fujita, M.; Takarada, Y.; Sugimura, T.; Tai, A. Chem. Commun.
1997, 1631-1632. (b) Sugimura, T.; Yamada, H.; Inoue, S.; Tai, A.
Tetrahedron: Asymmetry 1997, 8, 649-655.
the reaction with PTAD in CDCl3, cyclic acetal 12 was obtained
1
in the absence of methanol as shown in Figure 3. The H and
13C NMR spectra showed complete conversion of 3 to 12.
The reaction of PTAD with 4a in dichloromethane gave the
adduct 13a as a single diastereomer in 98% isolated yield. The

Asymmetric Addition of Electrophile to Naphthalenes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2949
Table 2. Isolated Yields and Enantiomeric Ratios of the Product
13 in Stereodifferentiating Addition of PTAD to 4 at 293 Ka
substrate
solvent
yield (%)b
enantiomeric ratioc
4a
4a
4a
4b
4c
4d
4e
benzene
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
98
98
81
96
93
94
71
97:3
96:4
96:4
98:2
95:5
95:5
91:9
a The adduct 13 is obtained as a single diastereomer (de > 98%)
1
determined by H NMR. b Product yield isolated by column chroma-
tography. c Enantiomeric ratio was determined by HPLC with a chiral
column (Daicel CHIRALPAK AD).
Table 3. Stereoselectivity in the Reaction of 5-7 with PTAD at
293 K
diastereomeric
Figure 3. Reaction of PTAD (132 mM) with 3 (68 mM) in CDCl3 at
293 K, monitored by H NMR: 3 (O) and 12 (b).
PTAD (equiv) solvent time (min) yield (%)
ratioa
1
5
1.7
1.2
2.1
1.9
1.9
C6H6
180
60
60
344
37
95b
91b
94b
88
95:5
95:5
95:5
94:6
96:4
Scheme 4
CH2Cl2
CH3CN
C6D6
CDCl3
97
6
340
120
68
123
240
432
9
1.7
1.2
6.9
6.9
6.9
6.9
7.1
7.1
7.1
C6H6
CH2Cl2
C6D6
C6D6
C6D6
63b,c
85b
27
44
70
92
27
71
97
74:26
72:28
82:18d
79:21d
76:24d
73:27
85:15d
76:24d
70:30
Scheme 5
C6D6
CDCl3
CDCl3
CDCl3
34
91
7
74
1.7
CDCl3
84
95:5
a 14-Si-syn/14-Si-anti for 5, 15-Si-syn/15-Si-anti for 6, and 16-Si-
syn/16-Si-anti for 7. b Isolated yield. c Substrate 6 was recovered (18%).
d Transient product 19 was also detected. Yields and ratios were the
values excluding 19.
The diastereomeric ratio of adducts 14-16 obtained under
various conditions are summarized in Table 3. In the case of 6,
the diastereomeric ratio of the adduct 15 (85% isolated yield)
obtained in CH2Cl2 was 15-Si-syn:15-Si-anti:15-Re-syn:15-Re-
anti ) 72:28:∼0:∼0.34 The diastereomeric ratio of 15 decreased
with the progress of the reaction. Substrate 7, a stereoisomer of
4a, also gave a high diastereomeric ratio (16-Si-syn:16-Si-anti
) 95:5).34
Stereochemistry of the Products. (1) Stereochemistry of
14. The configuration of the major isomer of 14 was determined
on the basis of chemical transformations in conjunction with
the NOE measurements as illustrated in Scheme 5. The NOE’s
observed for the diol 17, which was derived from 14 by OsO4
oxidation,14a,35 establish the configurations of the major isomer
of 14 as depicted in Scheme 6, 14-Si-syn. Acid hydrolysis of
14 gave levorotatory enone 18. Thus, (-)-enone 18 has the R
configuration at C-4. The minor diastereomer of 14 has the same
1H NMR spectrum as that of the major isomer of adduct 15
obtained from 6. The major isomer of 15 is 15-Si-syn (see
1H NMR spectrum of 13a shows that it is diastereomerically
pure, and the enantiomeric ratio of 13a was determined to be
96:4 by chiral HPLC. Possible stereoisomers of 13a include
two enantiomeric pairs of the diastereomers 13a-Si-syn/13a-
Si-anti and 13a-Re-syn/13a-Re-anti, as shown in Scheme 5,
because 13a-Si-syn and 13a-Re-syn are mirror images of 13a-
Si-anti and 13a-Re-anti, respectively. The formation of a single
diastereomer results from high stereoselectivity at C-1. The
enantiomeric ratio also indicates the high stereoselectivity at
C-4. The results translate to the product ratio of 13a-Si-syn:
13a-Si-anti:13a-Re-syn:13a-Re-anti ) 96:4:∼0:∼0 (see below).
The stereoselectivities at C-1 and C-4 remain high in benzene
and acetonitrile solutions. The electrophilic addition of PTAD
to the other substrates 4b-e also gave single diastereomeric
adducts with high enantiomeric ratios (Table 2).
(34) The adducts 14 and 15 possibly consist of four diastereomers 14-
Si-syn/14-Si-anti /14-Re-syn/14-Re-anti and 15-Si-syn/15-Si-anti/15-Re-
syn/15-Re-anti, respectively. In the case of 16, the possible isomers are
only two diastereomers, because 16-Si-syn and 16-Si-anti are identical to
16-Re-anti and 16-Re-syn, respectively. The ratios were determined by the
measurement of the peak area of the olefinic protons obtained by 1H NMR.
(35) (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. J. Am. Chem. Soc. 1988,
110, 621-622. (b) Poli, G. Tetrahedron Lett. 1989, 30, 7385-7388.
The reaction of 5 in CH2Cl2 gave 14 (91% yield) with a high
diastereomeric ratio (14-Si-syn:14-Si-anti:14-Re-syn:14-Re-anti
) 95:5:∼0:∼0).34 Other substrates 6 and 7 gave similar results.

2950 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Fujita et al.
Scheme 6
Figure 4. Reaction of PTAD (148 mM) with 5 (78 mM) in CDCl3 at
1
293 K, monitored by H NMR: 5 (O), 14-Si-syn (b), and 14-Si-anti
(4).
below), which is the enantiomer of 14-Si-anti. Proton NMR
signals other than those due to 14-Si-syn and 14-Si-anti were
not observed for 14 either when isolated or in the reaction
mixture. Thus, the diastereomeric ratio 14-Si-syn:14-Si-anti:
14-Re-syn:14-Re-anti was determined as 95:5:∼0:∼0.
(2) Stereochemistry of 13a. The NOE between the olefinic
proton and the methine protons of 13a indicates that the hydroxy
group of the side chain attacks C-1 from the Si-Re face of the
naphthalene core (13a ) 13a-Si-syn and 13a-Si-anti). Hydroly-
sis of 13a also gave (R)-(-)-enone 18, indicating that the
addition of PTAD at C-4 proceeds from the Si-Re face
preferentially. From these results, the configration of the major
Figure 5. Plot of ln{[5]/([PTAD]0 - [5]0 + [5])} vs time for the
electrophilic addition of PTAD (148 mM) to 5 (78 mM) in CDCl3 at
293 K.
1
isomer of 13a is determined to be 13a-Si-syn. The H NMR
spectrum of 13a indicates that it consists of a single diastere-
omer, and the chiral HPLC indicates that the enantiomeric ratio
of 13a is 96:4. In summary, the isomeric ratio is 13a-Si-syn:
13a-Si-anti:13a-Re-syn:13a-Re-anti ) 96:4:∼0:∼0.
it should be noted that 16-Si-syn ) 16-Re-anti and 16-Si-anti
) 16-Re-syn; that is, there are only two possible diastereomers
of 16.
(3) Stereochemistry of 15. The minor diastereomer of 15
has the same 1H NMR spectrum as that of the major adduct of
14 () 14-Si-syn), which is the enantiomer of 15-Si-anti. The
major isomer of 15 also shows an NOE between the olefinic
proton and the methine proton of the acetal ring. This indicates
that the major isomer of 15 is formed by attack of the alcohol
at C-1 from the Si-Re face (15-Si-syn or 15-Si-anti). Hydrolysis
of the diastereomeric mixture of 15 gave (R)-(-)-enone 18,
indicating that the addition of PTAD at C-4 proceeds prefer-
entially from the Si-Re face. The optical rotation of 18 obtained
from 15 of 48% de ([R]20D ) -82) is lower than that obtained
Kinetic Determinations. The electrophilic addition of PTAD
1
to 5 was monitored by H NMR at 293 K, and its time course
is shown in Figure 4. The decrease in [5] obeys second-order
kinetics,36 first order to both [5] and [PTAD], as shown by the
linear plot of ln{[5]/([PTAD]0 - [5]0 + [5])} vs time37a in Figure
5. From the slope of the linear plot and initial concentrations
of 5 and PTAD ([5]0 and [PTAD]0), the second-order rate
constant k was determined to be 2.1 × 10-2 M-1 s-1. The rate
constants k for the reaction of 3-7 are summarized in Table 4.
The ratio 14-Si-syn/14-Si-anti is constant during the reaction
of 5, indicating that these isomers are formed by parallel
kinetically controlled processes. Thus, the rate constant k for
the decrease of the substrate is resolved into the rate constants
for the formations of isomeric products (k1 and k2) using the
product ratio.
from 13a ([R]20 ) -154). The smaller optical rotation is
D
consistent with the lower diastereomeric purity of 15, 15-Si-
syn:15-Si-anti ) 74:26. Thus, the major isomer of 15 is 15-
Si-syn. Diastereomeric signals other than those of 15-Si-syn and
1
15-Si-anti were not observed in the H NMR of 15 isolated.
Thus, the diastereomeric ratio of 15 in benzene is determ-
(36) The reaction of 5 was too fast to determine k accurately under the
pseudo-first-order reaction conditions ([PTAD] . [5]) by 1H NMR. In the
case of 6, k values were determined at various concentrations of PTAD.
ined to be 15-Si-syn:15-Si-anti:15-Re-syn:15-Re-anti
)
1
74:26:∼0:∼0 by H NMR.
The 103k (M-1 s-1) values were 4.9, 5.0, and 5.0 when [PTAD]0/[6]0
4.2, 7.1, and 13, respectively.
)
1
(4) Stereochemistry of 16. The H NMR spectrum of 16
shows that it is a mixture of two diastereomers, and its
hydrolysis gave again (R)-(-)-enone 18. Thus, the diastereo-
meric ratio 16-Si-syn:16-Si-syn is determined to be 95:5. Here,
(37) Moore, J. W.; Pearson, R. G. In Kinetics and Mechanism, third
eddition; John Wiley & Sons: New York, 1981; (a) pp 22-25, (b) pp 290-
296. The integrated kinetic equations are modified for the parallel reaction.

Asymmetric Addition of Electrophile to Naphthalenes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2951
Table 4. Second-Order Rate Constants (k) for Electrophilic
Addition of PTAD to Several Substrates in Various Solvents at
293 K
Scheme 7
a
103k (M-1 s-1
)
substrate
C6D6
1.0
CDCl3
CD2Cl2
26
CD3CN
2.9
4a
4b
4c
4d
4e
5
6
7
3
15
47
10
0.067
>300b
21
5.0
10
4.7
2.1
0.68
26
2.0
2.2
a The experimental errors are (10%. b Too fast to be determined
Table 5. Rate Constants for the Elementary Steps in the Reaction
of 6 with PTAD at 293 K
1
accurately by H NMR.
solvent
k1 (M-1 s-1
)
k2 (M-1 s-1
)
k3 (s-1
)
C6D6
CDCl3
CDCl3
CD2Cl2
4.9 × 10-4
3.5 × 10-3
1.5 × 10-3
1.4 × 10-3
1.9 × 10-4
1.5 × 10-3
5.4 × 10-4
5.7 × 10-4
3.0 × 10-4
1.7 × 10-3
2.8 × 10-4
8.3 × 10-4
a
a In the presence of pyridine (48 mM).
Figure 6. Reaction of PTAD (135 mM) with 6 (19 mM) in CDCl3 at
1
293 K, monitored by H NMR: 6 (O), 15-Si-syn (b), 15-Si-anti (4),
and 19 (2). Solid lines show theoretical curves calculated from the
rate constants given in Table 5.
In the case of 6, the product ratio 15-Si-syn/15-Si-anti
changes with time and the reaction does not consist of simple
parallel processes (Table 3 and Figure 6). The curvatures of
the plots for the conversion of 6 and formation of 15-Si-syn
are smooth and follow pseudo-first-order kinetics with the same
half-life. However, the increase in 15-Si-anti follows an
S-shaped curve. The 1H NMR spectra show formation of a third
transient intermediate 19. Although 19 could not be isolated
from the reaction mixture to allow full structural characteriza-
Figure 7. Reaction of PTAD (194 mM) with 6 (26 mM) in the presence
of pyridine (48 mM) in CDCl3 at 293 K, monitored by H NMR: 6
(O), 15-Si-syn (b), 15-Si-anti (4), and 19 (2). Solid lines show
theoretical curves calculated from the rate constants given in Table 5.
1
Discussion
Stereochemistry of the Electrophilic Addition. Methanol
promotes the addition of PTAD to 1 to give adduct 8 rapidly,
but the reaction does not proceed to completion because of the
instability of 8. Adduct 8 decomposes back to 1, but the reaction
is not fully reversible due to the decay of PTAD. This was
confirmed by the methoxy exchange with CD3OD and ac-
companying loss of 8(9). The adduct 9 initially formed from 1
and PTAD in the presence of CD3OD is a single diastereomer
despite the possibility of the cis and trans isomers (Scheme 3).
However, epimerization of the adduct was observed as the
reaction progresses probably due to the secondary reaction of
2 with CH3OD generated by the methoxy exchange. The bis-
(deuteriomethoxy)adduct 10 was also formed. These results
indicate that subsequent decomposition of the adduct lowers
not only the chemical yield of the adduct but also the
stereoselectivity. Although the configuration of the first-formed
diastereomeric adduct 9 could not be determined due to its
instability and facile epimerization, the high stereoselectivity
1
tion, the H NMR spectrum of the reaction mixture shows
olefinic protons at 6.35 and 6.15 ppm and a high-field shift of
the 4-methyl group (2.03 ppm) for 19; this suggests that 19 is
a product of 1,4-addition to the naphthalene ring. The sum of
15-Si-anti and 19 fits well the first-order curve with the same
half-life as that for 6 and 15-Si-syn. These results strongly
suggest that the minor diastereomer 15-Si-anti is formed via
19 as an intermediate (Scheme 7). The curvatures for 19 and
15-Si-anti can be treated as a typical consecutive reaction, 6 f
19 f 15-Si-anti. Integrated forms of the kinetic equations for
time-dependent changes of [19] and [15-Si-anti]37b were
simulated by a nonlinear least-squares method on a personal
computer to give reasonable rate constants k3 (Table 5). Typical
simulation curves are shown in Figure 6.
The rate constant for conversion of 19 to 15-Si-anti, k3, is
decreased by added pyridine (Figure 7). Although the other rate
constants, k1 and k2, also become slightly smaller,38 the lifetime
of the transient product 19 is clearly prolonged by a base.
(38) The decrease in k1 and k2 in the presence of pyridine are ascribed
to interference by pyridine with the hydrogen-bonding interactions.

2952 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Fujita et al.
Scheme 8
Scheme 9
Scheme 10
of the addition of PTAD and methanol to 1 is evident from
results obtained in the initial stages of the reaction (Table 1).
Among the three conceivable pathways for the electrophilic
addition illustrated in Scheme 8, a simple trapping of the
naphthalenium intermediate by a free methanol molecule (Path
A) cannot explain the stereoselectivity.39 Immediate trapping
of a transient Diels-Alder adduct by methanol via the SN2
pathway should result in anti stereoselectivity (Path B).39 In
contrast, the syn adduct should be formed by a concerted process
of electrophilic addition of PTAD at C-4, proton transfer from
alcohol to PTAD, and nucleophilic attack at C-1 of the
naphthalene core by the alcohol (Path C). Thus, the relative
configuration (cis or trans) of the adduct is key evidence
regarding the role of alcohol in the electrophilic addition of
PTAD to naphthalene. It is reasonable that the electrophilic
addition and nucleophilic trapping by methanol proceed in a
syn fashion (Path C) by analogy with the syn addition observed
for the internal alcohols 4-6 (see below). Moreover, promotion
of the reaction by methanol is compatible with Path C.
When an internal alcohol function is introduced to the alkoxy
side chain of the substrate, quantitative formation of the adduct
is observed in the absence of an external alcohol. The adducts
obtained from 4-6 are stable enough to be isolated in 71-
98% yield. The electrophilic addition of PTAD to 4a yields
13a-Si-syn, 13a-Si-anti 13a-Re-syn, and 13a-Re-anti in a ratio
of 96:4:∼0:∼0. The major isomer 13a-Si-syn is formed by the
syn attack of PTAD and the internal alcohol from the Si-Re
face. This mode of reaction is preferred in all the electrophilic
additions of PTAD to 4a, 5, and 6.
The syn selectivity can reasonably be explained by the
concerted addition mechanism (Path C in Scheme 8). The
transition states for concerted formation of 13a are illustrated
in Scheme 9. The Si-Re face preference may be attributed to
the steric repulsion between the peri-hydrogen of the naphtha-
lene core and the cyclic acetal moiety in the alternative mode,
Re-Si face attack.40 When the steric repulsion is avoided in the
transition state for the Re-Si face attack, the methyl groups of
the side chain are forced to the axial positions (Scheme 9). In
fact, the acetal 15-Re-syn formed by the Re-Si attack to 6 is
unstable and easily isomerizes to 15-Si-anti, whose acetal moiety
corresponds to the adduct obtained by the Si-Re attack (see
below in Scheme 10). Adam and co-workers5 have reported the
directing ability of an alcohol in [4 + 2] addition and ene
reactions of PTAD to alkenes. The directing ability of an alcohol
has also been shown in endoperoxide formation from naphtha-
lenes and singlet oxygen.6 Singlet oxygen and PTAD are
suggested to have a similar electrophilic reactivity.26 In these
addition reactions, it was suggested that the stereoselectivities
are achieved by the hydrogen-bonding interactions between the
alcohol and the electrophile.
If the electrophilic addition of PTAD to 4-6 proceeds via
stereocontrolled [4 + 2] addition followed by the nucleophilic
substitution by the internal alcohol, the anti adduct should be
formed preferentially by the SN2 pathway (Scheme 8, Path B).
Formation of the syn adduct is only possible via the stereocon-
trolled [4 + 2] addition if the retention of configuration occurs
in the nucleophilic substitution step. This possibility is not
strictly excluded; the retained substitution by the alcohol may
be achieved when proton transfer from the alcohol to the PTAD
moiety of the [4 + 2] adduct acts as a driving force for the
substitution and the concerted nucleophilic trapping by the same
alcohol. Furthermore, the formation of the [4 + 2] addition
should have been in the equilibrium lying toward the substrate
if it occurred, since the reaction of 1 with PTAD was not
observed in the absence of alcohol.
In contrast to these less likely possibilities, a direct concerted
process is most reasonable for the syn selectivity (Scheme 8,
Path C). In the rate-determining step, the three events take place
in concert: (1) the electrophilic addition of PTAD, (2) proton
transfer from alcohol to PTAD, and (3) nucleophilic addition
of the alcohol. In other words, an anionic part of the zwitterionic
intermediate41 is stabilized by hydrogen-bonding interactions
with alcohol and the cationic part receives the nucleophilic
addition of the alcohol. The hydrogen-bonding interaction must
(39) Stereochemical considerations on 1,2-addition of PTAD and metha-
nol to olefin have been reported in ref 30g.
(40) Similar reactions have been reported: (a) Fujita, M.; Ohshiba, M.;
Yamasaki. Y.; Sugimura, T.; Tai, A. Chem. Lett. 1999, 139-140. (b) Fujita,
M.; Ohshiba, M.; Shioyama. S.; Sugimura, T.; Tai, A. Chem. Commun.
1998, 2243-2244.

Asymmetric Addition of Electrophile to Naphthalenes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2953
exist before the formation of the C-N bond and act as a driving
force for the addition, judging from the directing ability of the
alcohol in the electrophilic addition. The hydrogen-bonding
interaction in the transition state will be stronger than that in
[4 + 2] cycloadditions5,6 due to the polar transition state of
electrophilic addition.
could not be observed during the electrophilic addition to 4 and
5 because of the low yield of the minor adduct.
The degree of the stereoface differentiation of Si-Re vs Re-
Si is controlled by the side chain. The R-methyl group of the
alkoxy side chain largely dictates the stereodifferentiation, since
both 5 and 7 show stereoselectivity comparable to 4a. The
γ-methyl group of 6 also helps the preferential addition from
the Si-Re face. In this case, stereodifferentiating addition occurs
at C-4 which is as remote as 7 bonds from the stereogenic center.
Thus, both stereogenic centers of the (1S,3R)-3-hydroxy-1-
methylbutoxy side chain work together to achieve highly
stereodifferentiating addition from the Si-Re face.
Comparison of the Reaction Rate Constants. The rate
constants summarized in Table 4 show the effects of substituents
at C-4 and the alkoxy side chain as well as the effect of the
solvent. 4-Alkyl-substituted 4a-c undergo a slow addition
compared with 4e despite the electron-donating ability of alkyl
groups. These results indicate an important steric contribution
to the rate of the electrophilic addition. The reactivity of
4-phenyl-substituted substrate 4d is very small, probably due
to the steric effects of the phenyl group perpendicular to the
naphthalene ring as well as the electron-withdrawing effect of
the phenyl group.
A lower reactivity is observed for the substrate with a primary
alkoxy side chain (3 and 6) compared with 4a, 5, and 7. This
indicates that the R-methyl group effectively accelerates cy-
clization by the Thorpe-Ingold effect,43 i.e., the alkyl substitu-
tion in the side chain makes the entropy change in ring closure
more favorable.
The rates in chloroform and dichloromethane are larger than
those in benzene. Polar solvents can promote generation of an
ionic or zwitterionic intermediate. The decrease in reactivity in
acetonitrile may be due to interference with the hydrogen-
bonding interactions at the transition state by the hydrogen-
bond-accepting ability of the solvent. The moderate solvation
needed to stabilize the polar transition state without interference
with the hydrogen-bonding interactions appears to afford the
highest reactivity.
Mechanism for Formation of the Minor Diastereomer. It
was found from the time course of electrophilic addition to 6
that the minor product 15-Si-anti is formed via the transient
product 19. Two alternative structures are possible for the
intermediate 19: [4 + 2] cycloadduct 19x and the epimer (15-
Re-syn) of 15-Si-anti (Scheme 10). The cycloadduct 19x can
be formed by the [4 + 2] addition of PTAD from the Re-Si
face and then undergo an intramolecular attack of the hydroxy
group to give 15-Si-anti. However, the [4 + 2] adduct of PTAD
to 1 could not be detected at all in the absence of methanol.
This result excludes 19x as a candidate for the transient product
19.
On the other hand 15-Re-syn is formed by the syn attack of
PTAD and the internal alcohol from the Re-Si face. The
conversion of 15-Re-syn to 15-Si-anti can be achieved by the
intramolecular acetal exchange that causes epimerization at the
spiro carbon (C-1). The stabilization of 19 by pyridine conforms
to this mechanism of conversion of 15-Re-syn to 15-Si-anti.
Thus, the transient product 19 is presumably the epimer 15-
Re-syn, which is generated by the syn addition of PATD and
the intramolecular alcohol of 6 from the Re-Si face. This implies
that the syn selectivity of the PTAD addition to 6 is achieved
completely in the initial stage of both major and minor pathways,
the former from the Si-Re face attack to give 15-Si-syn and the
latter from the Re-Si face attack to give 15-Re-syn which is
then converted to 15-Si-anti. Thus, the syn relationship between
the alcohol and PTAD is a key feature of the promotion of the
addition to the naphthalene. In other words, when the stereo-
differentiation of the nucleophilic attack is achieved, PTAD is
guided by the nucleophile to the same stereoface to result in
the stereoface-differentiating addition of PTAD.
Minor products also seem to be formed in the anti addition
of PTAD and the internal alcohol in the reactions of 4 and 5. A
similar mechanism involving an initial syn addition from the
Re-Si face followed by epimerization to give the final minor
product is most reasonable,42 although the isomerization pathway
In conclusion, the dual properties of an alcohol as a proton
donor and a nucleophile not only effectively promote the
electrophilic addition of PTAD to naphthalenes but also
stereochemically dictate syn addition. The asymmetric variant
for the electrophilic addition was also successfully achieved by
using a chiral side chain.
(41) (a) Fatiadi, A. J. Synthesis 1987, 749-789. (b) Sauer, J.; Sustmann,
R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779-807. (c) Sustmann, R.;
Lu¨cking, K.; Kopp, G.; Rese, M. Angew. Chem., Int. Ed. Engl. 1989, 28,
1713-1715. (d) Drexler, J.; Lindermayer, R.; Hassan, M. A.; Sauer, J.
Tetrahedron Lett. 1985, 26, 2559-2562. (e) Kataoka, F.; Shimizu, N.;
Nishida, S. J. Am. Chem. Soc. 1980, 102, 711-716. (f) Yamago, S.; Ejiri,
S.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 1993, 115, 5344-
5345.
(42) Alternative conceivable mechanisms for the formation of the minor
diastereomers in these cases are (A) direct formation via zwitterionic
intermediate, (B) [4 + 2] cycloaddition followed by immediate SN2 reaction,
(C) syn addition from the Re-Si face followed by epimerization of the acetal,
and (D) isomerization of the substrate followed by the syn addition.
Mechanism A is unlikely from the observed independence of the stereo-
selectivity of the solvent, since the ionic intermediate would be strongly
influenced by the medium. On the basis of the methoxy exchange results,
decomposition of the adduct possibly leads the isomerization of the substrate
(from 4 to enantiomer of 4, from 5 to the enantiomer of 6, and from 6 to
the enantiomer of 5) to result in the fall of the stereoselectivity of the adduct
(mechanism D). If the isomerization of 5 to the enantiomer of 6 occurred
during the electrophilic addition of PTAD to 5, formation of the enantiomer
of 6 should have been observed because the reaction of 6 is slower than
that of 5. Failure to observe isomerization of the substrate during the reaction
of 5 excludes mechanism D. Although it is difficult to exclude mechanism
B completely, mechanism C is more reasonable on the analogy of the
reaction of 6, which affords a relatively large amount of the minor
diastereomer.
Experimental Section
General. Proton and 13C NMR spectra were measured on a JEOL
1
EXcalibur-400 spectrometer as solutions in CDCl3. H NMR spectra
at 400 MHz were recorded using the residual CHCl3 as an internal
reference (7.24 ppm), and 13C NMR spectra at 100 MHz were recorded
using CDCl3 as an internal reference (77.00 ppm). Optical rotations
were measured on a Perkin-Elmer 243B polarimeter. Melting points
were measured on a Yanaco micro-melting-point apparatus and are
uncorrected. Infrared spectra were recorded on a Jasco IR-810 or FT/
IR-410 spectrometer. A JEOL JMS-AX505HA mass spectrometer was
used for MS. HPLC were conducted on a Hitachi L-6200 intelligent
pump with a chiral column (Daicel CHIRALPAK AD, 0.46 φ × 25
cm) and were monitored using a Shimadzu SPD-10A UV-vis detector
and a Jasco OR-990 chiral detector. 4-Phenyl-1,2,4-triazoline-3,5-dione
(43) (a) Kirby, A. J. In AdVances in Physical Organic Chemistry; Gold,
V., Bethell, D., Eds.; Academic Press: London, 1980; Vol. 17, pp 183-
278. (b) Jager, J.; Graafland, T.; Schenk, H.; Kirby, A. J.; Engberts, J. B.
F. N. J. Am. Chem. Soc. 1984, 106, 139-143. (c) DeTar, D. F.; Luthra, N.
P. J. Am. Chem. Soc. 1980, 102, 4505-4512. (d) Sternbach, D. D.; Rossana,
D. M.; Onan, K. D. Tetrahedron Lett. 1985, 26, 591-594.

2954 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Fujita et al.
(Aldrich) was used without further purification. 1-Methoxy-4-methyl-
naphthalene (1) was prepared according to the literature procedure.44
1-(Methoxy-d3)-4-methylnaphthalene (2) was prepared from 4-methyl-
1-naphthol and dimethyl-d6 sulfate (Aldrich). Acetonitrile and dichloro-
methane were distilled from calcium hydride. Benzene was purified
by distillation from sodium. Acetonitrile-d3, dichloromethane-d2,
benzene-d6, methanol-d4, and chloroform-d were obtained from Aldrich.
1-(3-Hydroxypropoxy)-4-methylnaphthalene (3). A solution of
4-methyl-1-naphthol (1.05 g, 6.6 mmol) and 3-bromo-1-propanol (1.8
mL) in acetone (10 mL) was refluxed in the presence of K2CO3 (4.9
g) for 4 h. The solution was cooled to room temperature, quenched by
H2O, and extracted with CH2Cl2. The combined organic extract was
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography (SiO2, eluent 30% EtOAc in hexane) to give 3 as
Scheme 11
1
a white solid (1.4 g, 100% yield): mp 94-97 °C (EtOAc); H NMR
(CDCl3) δ 8.24 (d, 1H, J ) 8.3 Hz), 7.90 (d, 1H, J ) 8.3 Hz), 7.52 (t,
1H, J ) 8.3 Hz), 7.47 (t, 1H, J ) 8.3 Hz), 7.17 (d, 1H, J ) 7.8 Hz),
6.72 (d, 1H, J ) 7.8 Hz), 4.26 (t, 2H, J ) 5.9 Hz), 3.96 (t, 2H, J ) 5.9
Hz), 2.59 (s, 3H), 2.17 (quint, 2H, J ) 5.9 Hz); 13C NMR (CDCl3) δ
153.3, 133.5, 126.3, 126.1, 126.0, 124.8, 124.0, 122.3, 104.9, 65.9,
60.5, 32.5, 18.7; IR (KBr) 3350, 2900, 1580, 1500, 1460, 1420, 1380,
1350, 1280, 1250, 1150, 1080, 1050, 800 cm-1; MS (EI) m/z (relative
intensity, %) 216 (53, M+), 158 (100); HRMS (EI) calcd for C14H16O2
(M) 216.1150, found 216.1153.
Typical Procedure for the Mitsunobu Reaction To Give (1′S,3′R)-
1-(3-Hydroxy-1-methylbutoxy)-4-methylnaphthalene (4a). To a solu-
tion of 4-methyl-1-naphthol (4.0 g, 25 mmol), Ph3P (6.6 g, 25 mmol),
and (2R, 4R)-2,4-pentanediol (3.0 g, 28 mmol) in THF (15 mL) was
added diethyl azodicarboxylate (4.0 mL, 25 mmol) dropwise at 0 °C.
The mixture was stirred overnight, quenched by a small amount of
H2O, and concentrated in vacuo. The residue was purified by chroma-
23.7, 20.0; MS (EI) m/z (relative intensity, %) 272 (25, M+), 186 (73),
171 (100); HRMS (EI) calcd for C18H24O2 (M) 272.1776, found
272.1783.
(1′S,3′R)-1-(3-Hydroxy-1-methylbutoxy)-4-phenylnaphthalene (4d).
The Mitsunobu reaction using 4-phenyl-1-naphthol (0.51 g) gave 4d
(0.60 g, 85% yield): [R]22D ) +66 (c 1.00 CHCl3); 1H NMR (CDCl3)
δ 8.39 (d, 1H, J ) 8.6 Hz), 7.83 (d, 1H, J ) 8.6 Hz), 7.54-7.42 (m,
7H), 7.37 (d, 1H, J ) 7.8 Hz), 7.00 (d, 1H, J ) 7.8 Hz), 4.94-4.87
(m, 1H), 4.21-4.13 (m, 1H), 2.67 (br, 1H), 2.23 (dt, 1H, J ) 14.6, 8.4
Hz), 1.85 (dt, 1H, J ) 14.6, 4.2 Hz), 1.48 (d, 3H, J ) 6.3 Hz), 1.31 (d,
3H, J ) 5.9 Hz); 13C NMR (CDCl3) δ 152.3, 140.7, 132.9, 132.7, 130.1,
128.1, 126.8, 126.7, 126.5, 126.4, 125.8, 125.1, 122.1, 106.2, 73.6,
66.8, 45.7, 23.9, 20.0; IR (film) 3400, 2980, 2930, 1720, 1580, 1510,
1460, 1380, 1240, 1110, 1070, 770, 700 cm-1; MS (EI) m/z (relative
intensity, %) 306 (19, M+), 220 (100), 122 (44); HRMS (EI) calcd for
C21H22O2 (M) 306.1620, found 306.1649.
tography (SiO2, eluent 40% EtOAc in hexane) to give 4a (5.5 g, 90%
1
yield): [R]20 ) +83 (c 1.05 CHCl3); H NMR (CDCl3) δ 8.23 (d,
D
1H, J ) 8.3 Hz), 7.91 (d, 1H, J ) 7.8 Hz), 7.51 (t, 1H, J ) 7.6 Hz),
7.45 (t, 1H, J ) 7.6 Hz), 7.18 (d, 1H, J ) 7.8 Hz), 6.80 (d, 1H, J )
7.8 Hz), 4.87-4.74 (m, 1H), 4.15-4.08 (m, 1H), 2.59 (s, 3H), 2.11
(dt, 1H, J ) 14.7, 7.1 Hz), 1.79 (ddd, 1H, J ) 14.7, 4.4, 3.4 Hz), 1.36
(d, 3H, J ) 5.9 Hz), 1.23 (d, 3H, J ) 6.3 Hz); 13C NMR (CDCl3)
151.1, 133.4, 126.6, 126.5, 126.1, 125.9, 125.0, 124.0, 122.3, 106.7
(Ar), 74.0, 67.1, 45.7, 23.9, 20.0, 19.0; IR (film) 3370, 3070, 2970,
2930, 1630, 1590, 1520, 1460, 1430, 1390, 1340, 1280, 1250, 1210,
1160, 1120, 1080, 1020, 960, 920, 820, 760 cm-1; MS (EI) m/z (relative
intensity, %) 244 (33, M+), 158 (100); HRMS (EI) calcd for C16H20O2
(M) 244.1463, found 244.1472.
(1′S,3′R)-1-(3-Hydroxy-1-methylbutoxy)naphthalene (4e). The
Mitsunobu reaction using 1-naphthol (0.70 g) gave 4e (0.83 g, 74%
yield): [R]22D ) +107 (c 1.01 CHCl3); 1H NMR (CDCl3) δ 8.20 (dd,
1H, J ) 6.8, 2.0 Hz), 7.78 (dd, 1H, J ) 6.8, 2.0 Hz), 7.46-7.33 (m,
4H), 6.90 (d, 1H, J ) 7.3 Hz), 4.86-4.78 (m, 1H), 4.15-4.08 (m,
1H), 2.43 (d, 1H, J ) 2.9 Hz, OH), 2.13 (ddd, 1H, J ) 14.1, 8.8, 5.8
Hz), 1.80 (dt, 1H, J ) 14.1, 3.9 Hz), 1.39 (d, 3H, J ) 5.9 Hz), 1.24 (d,
3H, J ) 5.7 Hz); 13C NMR (CDCl3) δ 152.8, 134.6, 127.5, 126.4, 126.3,
125.7, 125.3, 121.9, 120.5, 106.7, 73.7, 66.9, 45.7, 23.9, 19.9; IR (film)
3400, 3050, 2970, 2930, 1730, 1510, 1460, 1400, 1270, 1240, 1100,
800, 780 cm-1; MS (EI) m/z (relative intensity, %) 230 (14, M+), 144
(100); HRMS (EI) calcd for C15H18O2 (M) 230.1307, found 230.1328.
(1′S)-1-(3-Hydroxy-1-methylpropoxy)-4-methylnaphthalene (5).
Substrates, 5 and 6 were prepared according to Scheme 11. Methyl
(R)-3-hydroxybutanoate (5.1 g, 43 mmol) purchased from Kanto
Chemicals was treated with 3,4-dihydropyrane (4.3 g, 51 mmol) in Et2O
(15 mL) in the presence of a catalytic amount of TsOH. The mixture
was quenched by saturated NaHCO3 and extracted with ether (×3).
The combined organic extract was washed with brine, dried (Na2SO4),
and concentrated in vacuo to give the THP ether (10 g) as a crude oil.
The crude THP ether was reduced with LiAlH4 in ether. The mixture
was quenched by a small amount of H2O. The salt formed was removed
by filtration through a Celite pad and washed with ether. The filtrate
was concentrated in vacuo to give alcohol 20 (7.2 g, 41 mmol, 97%
yield) as an oil. To a solution of 20 (2.24 g, 12.9 mmol) in CH2Cl2 (10
mL) containing pyridine (2.1 mL) was added PhCOCl (2.2 mL) at 0
°C. After stirring for 2 h at room temperature, the mixture was quenched
with H2O and extracted with ether (×3). The combined extract was
washed with saturated CuSO4 and brine and then dried (Na2SO4) and
concentrated in vacuo. The residue was purified by chromatography
(SiO2, eluent 30% EtOAc in hexane) to give the benzoate 21 (3.54 g,
99% yield). To a solution of 21 (3.54 g) in MeOH was added TsOH-
pyridine, and the solution was stirred for 3 h. The solution was
concentrated in vacuo, and the residue was purified by chromatography
(SiO2, eluent 20-40% EtOAc in hexane, gradient) to give recovered
21 and alcohol 22 (1.37 g, 56% yield). The Mitsunobu reaction using
22 and 4-methyl-1-naphthol was performed in a similar manner to that
described for 4a to give 23 in 84% yield. The benzoate 23 (2.4 g, 7.2
(1′S,3′R)-1-(3-Hydroxy-1-methylbutoxy)-4-ethylnaphthalene (4b).
The Mitsunobu reaction using 4-ethyl-1-naphthol (3.08 g) gave 4b (3.53
1
g, 76% yield): [R]24 ) +92 (c 1.02 CHCl3); H NMR (CDCl3) δ
D
8.26 (d, 1H, J ) 7.8 Hz), 7.98 (d, 1H, J ) 7.8 Hz), 7.51 (t, 1H, J )
7.8 Hz), 7.45 (t, 1H, J ) 7.8 Hz), 7.21 (d, 1H, J ) 7.8 Hz), 6.84 (d,
1H, J ) 7.8 Hz), 4.81-4.76 (m, 1H), 4.14-4.08 (m, 1H), 3.02 (q, 2H,
J ) 7.5 Hz), 2.55 (s, 1H), 2.12 (dt, 1H, J ) 14.4, 8.6 Hz), 1.79 (dt,
1H, J ) 14.4, 3.7 Hz), 1.37 (d, 3H, J ) 5.7 Hz), 1.34 (t, 3H, J ) 7.5
Hz), 1.23 (d, 3H, J ) 6.3 Hz); 13C NMR (CDCl3) δ 151.2, 132.7, 132.6,
126.8, 126.1, 124.8, 124.4, 123.6, 122.5, 106.7, 73.8, 67.0, 45.7, 25.5,
23.8, 20.0, 15.2; IR (film) 3400, 2970, 2940, 2880, 1740, 1590, 1520,
1465, 1380, 1275, 1220, 1120, 820, 770 cm-1; MS (EI) m/z (relative
intensity, %) 258 (58, M+), 172 (100), 157 (76); HRMS (EI) calcd for
C17H22O2 (M) 258.1620, found 258.1642.
(1′S,3′R)-1-(3-Hydroxy-1-methylbutoxy)-4-isopropylnaph-
thalene (4c). The Mitsunobu reaction using 4-isopropyl-1-naphthol
(2.85 g) gave 4c (2.17 g, 52% yield): [R]20 ) +87 (c 1.08 CHCl3);
D
1H NMR (CDCl3) δ 8.31 (d, 1H, J ) 8.3 Hz), 8.09 (d, 1H, J ) 8.3
Hz), 7.53 (t, 1H, J ) 8.3 Hz), 7.47 (t, 1H, J ) 8.3 Hz), 7.31 (d, 1H,
J ) 7.8 Hz), 6.90 (d, 1H, J ) 7.8 Hz), 4.85-4.77 (m, 1H), 4.16-4.09
(m, 1H), 3.68 (sept, 1H, J ) 6.8 Hz), 2.69 (s, 1H), 2.14 (dt, 1H, J )
14.4, 8.6 Hz), 1.79 (dt, 1H, J ) 14.4, 3.7 Hz), 1.399 (d, 3H, J ) 6.8
Hz), 1.399 (d, 3H, J ) 6.8 Hz), 1.39 (d, 3H, J ) 5.9 Hz), 1.26 (d, 3H,
J ) 5.9 Hz); 13C NMR (CDCl3) δ 150.9, 136.8, 132.3, 126.7, 126.0,
124.7, 123.1, 122.5, 121.3, 106.6, 73.8, 67.0, 45.8, 28.2, 23.9, 23.7,
(44) Buu-Ho¨ı, N. P.; Lavit, D. J. Chem. Soc. 1955, 2776-2779.

Asymmetric Addition of Electrophile to Naphthalenes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2955
mmol) was hydrolyzed in EtOH (50 mL) in the presence of KOH (0.2
g) and H2O (2 mL). The mixture was quenched with H2O and extracted
with CH2Cl2 after evaporation of EtOH. The combined organic extract
was washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by chromatography (SiO2, eluent 35% EtOAc
of 1 (0.30 M) and PTAD (0.66 M) in CDCl3 was added CH3OH (0.49
M). The reaction was monitored at 293 K in the dark by H NMR.
Formation of adduct 8 (35% yield) was observed with an accompanying
decrease of 1 after 10 min. 8: 1H NMR (CDCl3) δ 8.20-6.94 (m,
9H), 6.39 (d, 1H, J ) 10.4 Hz), 6.14 (d, 1H, J ) 10.4 Hz), 3.15 (s,
3H), 3.11 (s, 3H), 1.98 (s, 3H).
1
in hexane) to give the title compound 5 as a colorless oil (1.31 g, 79%
1
yield): [R]20 ) +89 (c 0.78 CH2Cl2); H NMR (CDCl3) δ 8.25 (d,
Reaction of 1 with PTAD in the Presence of CD3OD. To a solution
of 1 (80 mM) and PTAD (275 mM) in CDCl3 was added CD3OD (1.0
D
1H, J ) 8.4 Hz), 8.10 (d, 1H, J ) 8.4 Hz), 7.52 (ddd, 1H, J ) 8.4,
6.8, 1.5 Hz), 7.46 (ddd, 1H, J ) 8.4, 6.8, 1.5 Hz), 7.18 (d, 1H, J ) 7.8
Hz), 6.80 (d, 1H, J ) 7.8 Hz), 4.82-4.76 (m, 1H), 3.90-3.86 (m,
2H), 2.59 (s, 3H), 2.16-2.09 (m, 1H), 2.01-1.95 (m, 1H), 1.80 (br,
1H), 1.39 (d, 3H, J ) 5.9 Hz); 13C NMR (CDCl3) δ 152.2, 133.8,
127.0, 126.3, 126.1, 126.1, 124.8, 124.0, 122.6, 106.9, 72.7, 60.0, 39.7,
20.0, 18.6; IR (film) 3350, 2950, 1720, 1580, 1380, 1280 cm-1; MS
(EI) m/z (relative intensity, %) 230 (39, M+), 158 (100); HRMS (EI)
calcd for C15H18O2 (M) 230.1307, found 230.1316. Racemic 5 was also
prepared using racemic methyl 3-hydroxybutanoate by the same
procedure.
1
M). The reaction was monitored at 293 K in the dark by H NMR.
Formation of adducts 9/10, 2, and CH3OD was observed with an
accompanying decrease of 1. The ratio of 1/2 was determined by
comparison of the peak areas due to the methoxy group (3.96 ppm)
and the 4-methyl group (2.59 ppm). The ratio of 9/10 was determined
by comparison of the peak areas due to the methoxy group (3.14 and
3.13 ppm) and methyl group (1.98 ppm). Formation of the dimethoxy
adduct 8 was neglected. The diastereomeric ratio of 9 was determined
by comparison of the peak areas due to the methoxy group (3.14 and
3.13 ppm). Determination of the composition of the naphthalenes and
the adducts was performed by comparison of the peak areas due to the
4-methyl groups of the 1/2 (2.59 ppm) and 9/10 (1.98 ppm). The amount
of CH3OD was determined by the peak area at 3.4 ppm. A time course
of the reaction is shown in Figure 1 and Table 1. 9: 1H NMR (CDCl3)
δ 8.20-6.94 (m, 9H), 6.39 (d, 1H, J ) 10.4 Hz), 6.14 (d, 1H, J )
10.4 Hz), 3.14 and 3.13 (s, 3H), 1.98 (s, 3H).
(3′R)-1-(3-Hydroxybutoxy)-4-methylnaphthalene (6). Using the
alcohol 20 (1.0 g) prepared above, the Mitsunobu reaction of 4-methyl-
1-naphthol was carried out to give 24 (1.1 g, 58% yield). Compound
24 (0.22 g, 0.7 mmol) was hydrolyzed in MeOH in the presence of
TsOH. The mixture was concentrated in vacuo and purified by
chromatography (SiO2, 25% EtOAc in hexane) to give 6 as a white
solid (0.16 g, 97% yield): mp 74.5-75.0 °C; [R]20 ) -14.9 (c 1.07
Reaction of 2 with PTAD in the Presence of CH3OH. To a solution
of 2 (128 mM) and PTAD (185 mM) in CDCl3 was added CH3OH
D
1
CH2Cl2); H NMR (CDCl3) δ 8.23 (d, 1H, J ) 7.8 Hz), 7.91 (d, 1H,
1
J ) 7.8 Hz), 7.52 (ddd, 1H, J ) 7.8, 7.3, 1.5 Hz), 7.46 (ddd, 1H, J )
7.8, 7.3, 1.5 Hz), 7.18 (d, 1H, J ) 7.8 Hz), 6.72 (d, 1H, J ) 7.8 Hz),
4.32-4.18 (m, 3H), 2.59 (s, 3H), 2.15-1.99 (m, 2H), 1.31 (d, 3H, J )
6.3 Hz); 13C NMR (CDCl3) δ 153.4, 133.6, 126.4, 126.2, 126.1, 124.9,
124.0, 122.4, 105.1, 105.0, 66.2, 66.2, 38.8, 23.9, 18.6; IR (KBr) 3300,
3060, 2900, 1800, 1590, 1280, 1090 cm-1; MS (EI) m/z (relative
intensity, %) 230 (94, M+), 158 (100); HRMS (EI) calcd for C15H18O2
(M) 230.1307, found 230.1304. Racemic 6 was also prepared by the
same procedure.
(254 mM). The reaction was monitored at 293 K in the dark by H
NMR. Formation of adduct 11 (15% yield) was observed after 6 min.
The ratio of peaks at 3.14 and 3.13 ppm was 29:71 at 6 min. The
diastereomeric ratio of 11 decreased with reaction time to be 43:57 at
25 min (23% yield).
Electrophilic Addition of PTAD to 3. To a solution of 3 (7.6 mg,
0.035 mmol, 68 mM) in CDCl3 (0.52 mL) in an NMR tube was added
PTAD (12 mg, 0.068 mmol, 132 mM). The mixture was allowed to
stand for 70 min at 293 K in the dark to give adduct 12 in 80% yield.
1
The product 12 was characterized by H and 13C NMR spectroscopy:
(1′S,3′S)-1-(3-Hydroxy-1-methylbutoxy)-4-methylnaphthalene (7).
To a solution of 4a (2.0 g, 8.3 mmol), Ph3P (2.6 g, 9.8 mmol), and
benzoic acid (1.24 g, 10.1 mmol) in THF (12 mL) was added diethyl
azodicarboxylate (1.8 mL, 11.5 mmol) dropwise at 0 °C. The mixture
was stirred overnight, quenched by a small amount of H2O, and
concentrated in vacuo. The residue was purified by chromatography
(SiO2, eluent 30% EtOAc in hexane) to give (2S,4S)-2-benzoyloxy-4-
(4-methyl-1-naphthoxy)pentane (2.16 g, 74.8% yield): 1H NMR
(CDCl3) δ 8.25 (d, 1H, J ) 8.8 Hz), 7.98 (d, 2H, J ) 7.3 Hz), 7.87 (d,
1H, J ) 8.3 Hz), 7.54-7.46 (m, 2H), 7.42-7.37 (m, 3H), 7.09 (d, 1H,
J ) 7.8 Hz), 6.66 (d, 1H, J ) 7.8 Hz), 5.43-5.38 (m, 1H), 4.74-4.70
(m, 1H), 2.55 (s, 3H, Me), 2.24-2.11 (m, 2H), 1.43 (d, 3H, J ) 6.4
Hz), 1.39 (d, 3H, J ) 5.9 Hz). The benzoate (2.16 g, 6.19 mmol) was
hydrolyzed in aqueous methanol containing KOH at 35 °C for 8 h.
The reaction mixture was extracted with CH2Cl2, and the organic
extracts were evaporated in vacuo. The resulting residue was purified
by chromatography (SiO2, eluent 30% EtOAc in hexane) to give 7 as
a white solid (1.27 g, 84.2% yield): [R]20D ) +87 (c 1.02 CHCl3); mp
51.3-53.0 °C; 1H NMR (CDCl3) δ 8.24 (d, 1H, J ) 8.3 Hz), 7.90 (d,
1H, J ) 8.3 Hz), 7.51 (t, 1H, J ) 7.1 Hz), 7.45 (t, 1H, J ) 6.8 Hz),
7.18 (d, 1H, J ) 7.8 Hz), 6.80 (d, 1H, J ) 7.8 Hz), 4.87-4.82 (m,
1H), 4.19-4.18 (m, 1H), 2.59 (s, 3H, Me), 1.98 (ddd, 1H, J ) 14.7,
8.8, 2.9 Hz), 1.85-1.79 (m, 2H), 1.38 (d, 3H, J ) 5.9 Hz), 1.25 (d,
3H, J ) 6.4 Hz); 13C NMR (CDCl3) δ 152.0, 133.5, 126.5, 126.1, 126.0,
124.8, 124.0, 122.4, 106.2, 71.7, 64.8, 45.9, 24.2, 20.0, 18.9; IR (KBr)
3300, 2690, 2920, 1590, 1520, 1470, 1430, 1380, 1340, 1280, 1250,
1230, 1160, 1110, 1080, 1040, 020, 820, 770, 740 cm-1; MS (EI) m/z
(relative intensity, %) 244 (61, M+), 158 (100); HRMS (EI) calcd for
C16H20O2 (M) 244.1463, found 244.1480. Anal. Calcd for C16H20O2:
C, 78.65; H, 8.25. Found: C, 78.53; H, 8.26.
1H NMR (CDCl3) δ 7.89 (d, 1H, J ) 6.9 Hz), 7.54-7.27 (m, 8H),
7.03 (d, 1H, J ) 10.8 Hz), 6.22 (d, 1H, J ) 10.8 Hz), 4.30-4.20 (m,
2H), 4.03-3.91 (m, 2H), 2.35-2.27 (m, 1H), 2.03 (s, 3H), 1.54 (d,
1H, J ) 13.2 Hz); 13C NMR (CDCl3) δ 152.7, 152.1, 137.0, 136.6,
131.0, 129.8, 129.3, 128.9, 128.7, 127.4, 125.6, 124.7, 123.9, 123.6,
91.0, 61.2, 61.0, 61.0, 28.0, 25.5.
General Procedure of Electrophilic Addition of PTAD to
Naphthalenes 4a-e. A sample of PTAD (36 mg, 0.21 mmol, 1.3 equiv)
was added to a solution of 4a (40 mg, 0.16 mmol) in CH2Cl2 (2 mL).
After stirring at room temperature for 30 min, the solution was
concentrated in vacuo. The residue was purified by chromatography
(SiO2, eluent 60% EtOAc in hexane) to give 13a (67 mg, 98% yield).
1
No other diastereomeric isomer of 13a was detected in the H NMR
spectrum of the isolated sample or of the crude mixture. 1H NMR
monitoring of the reaction of 4a with PTAD in CDCl3 also indicates
formation of the single diastereomer of 13a. The enantiomeric ratio
was determined by HPLC with a chiral column using both UV-vis
and polarimetric detectors. A mixed solvent of hexane and 2-propanol
(95:5 v/v) was used as an eluent at a flow rate of 0.5 mL/min. Peak
areas were measured at 260 nm. The peaks were confirmed to be due
to the enantiomeric products by optical rotation and by the co-injection
of the enantiomeric adduct prepared from the enantiomeric substrate,
which was obtained from (2S,3S)-2,4-pentandiol. The retention times
of the major (13a-Si-syn) and minor (13a-Si-anti) enantiomers of 13a
were 38.9 and 35.8 min, respectively, and the ratio of peak areas was
1
96:4. 13a: mp 96-98 °C; [R]20 ) -98 (c 1.02 CH2Cl2); H NMR
D
(CDCl3, 400 MHz) δ 7.89 (d, 1H, J ) 6.8 Hz), 7.57 (d, 1H, J ) 6.8
Hz), 7.48-7.40 (m, 6H), 7.34 (t, 1H, J ) 6.8 Hz), 6.96 (d, 1H, J )
10.8 Hz), 6.20 (d, 1H, J ) 10.8 Hz), 4.31-4.25 (m, 2H), 2.02 (s, 3H),
1.66 (d, 1H, J ) 13.2 Hz), 1.44 (q, 1H, J ) 13.2 Hz), 1.24 (d, 3H, J
) 5.8 Hz), 1.22 (d, 3H, J ) 6.4 Hz); 13C NMR (CDCl3, 100 MHz) δ
152.3, 151.8, 137.5, 136.5, 131.6, 131.1, 129.4, 128.9, 128.8, 127.9,
127.4, 125.5, 125.4, 124.7, 91.8, 66.8, 66.4, 60.9, 40.4, 27.8, 22.3, 22.3;
Reaction of 1 with PTAD in the Absence of CH3OH. A solution
of 1 (0.32 M) and PTAD (0.39 M) in CDCl3 was prepared by mixing.
After 8 h at 293 K in the dark, most of the substrate 1 remained,
although a trace amount of enone 18 and methanol were detected (<5%
yield) presumably from H2O in the CDCl3.
IR (film) 3200, 2980, 1780, 1700, 1600, 1500, 1420, 1300, 1250 cm-1
MS (EI) m/z (relative intensity, %) 419 (0.3, M+), 244 (20, M -
;
Reaction of 1 with PTAD in the Presence of CH3OH. To a solution

2956 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Fujita et al.
PTAD+), 158 (100). Anal. Calcd for C24H25O4N3: C, 68.78; H, 6.01;
N, 10.02. Found: C, 68.99; H, 6.00; N, 10.11.
evaporated in vacuo. The residue was purified by chromatography (SiO2,
eluent 75% EtOAc in hexane) to give 18 (39 mg, 71% yield). Although
the enantiomeric ratio of 18 could not be determined by chiral HPLC
analysis, the optical rotation value and comparison of it with the value
obtained from 14-16 suggest retention of stereochemical purity at C-4
after the hydrolysis: [R]20D ) -154 (c 0.76 CH2Cl2); 1H NMR (CDCl3)
δ 8.18 (d, 1H, J ) 7.3 Hz), 7.71 (d, 1H, J ) 7.3 Hz), 7.66 (t, 1H, J )
7.3 Hz), 7.51-7.35 (m, 6H), 7.05 (d, 1H, J ) 10.2 Hz), 6.54 (d, 1H,
J ) 10.2 Hz), 2.07 (s, 3H); 13C NMR (CDCl3) δ 153.4, 153.4, 146.3,
142.9, 133.7, 130.8, 130.6, 130.0, 129.0, 128.8, 128.4, 127.4, 125.6,
125.5, 61.2, 27.6; IR (film) 3400, 2950, 1700, 1600, 1500, 1420, 1300
cm-1; MS (EI) m/z (relative intensity, %) 333 (18, M+), 177 (43), 158
(100); HRMS (EI) calcd for C19H15O3N3 (M) 333.1113, found 333.1118.
Electrophilic Addition of PTAD to 5 To Give 14. A sample of
PTAD (180 mg, 1.03 mmol, 1.2 equiv) was added to a solution of 5
(192 mg, 0.84 mmol) in CH2Cl2 (4 mL). After stirring at room
temperature for 1 h, the solution was concentrated in vacuo. The residue
was purified by chromatography (SiO2, eluent 75% EtOAc in hexane)
to give 14 (308 mg, 91% yield). No products other than 14-Si-syn and
14-Si-anti were detected by NMR either in the isolated sample or the
crude mixture. The diastereomeric ratio of compound 14 was determined
by measurement of peak areas for the olefinic protons in the 6.2 ppm
region of the H NMR spectrum as 95:5. The H NMR of the minor
diastereomer 14-Si-anti was the same as that of the major product (15-
Si-syn) from 6. The diastereomeric mixture of 14 (14-Si-syn:14-Si-
anti ) 95:5) had an optically rotation of [R]20D ) -83 (c 0.96 CH2Cl2).
14-Si-syn: 1H NMR (CDCl3) δ 7.87 (d, 1H, J ) 7.8 Hz), 7.52 (d, 1H,
J ) 7.8 Hz), 7.46-7.32 (m, 7H), 6.97 (d, 1H, J ) 10.8 Hz), 6.19 (d,
1H, J ) 10.8 Hz), 4.30-4.24 (m, 1H), 4.23-4.18 (m, 1H), 3.98 (dd,
1H, J ) 12.5, 5.2 Hz), 2.03 (s, 3H), 1.87 (qd, 1H, J ) 12.5, 5.2 Hz),
1.63-1.57 (m, 1H), 1.20 (d, 3H, J ) 5.9 Hz); 13C NMR (CDCl3) δ
152.6, 152.1, 137.2, 136.5, 131.5, 131.1, 129.4, 128.9, 128.7, 128.0,
127.5, 125.5, 124.6, 124.3, 91.5, 66.4, 61.2, 61.1, 32.9, 27.9, 22.5; IR
(film) 3450, 2950, 1700, 1600, 1500, 1400, 1300, 1250, 1100, 1020,
770, 660 cm-1; MS (EI) m/z (relative intensity, %) 230 (18, M -
PTAD+), 158 (100).
13b. A similar procedure to that used for the electrophilic addition
using 4b (51 mg, 0.20 mmol) and PATD (52 mg, 0.30 mmol, 1.5 equiv)
gave 13b (83 mg, 96% yield) as a single diastereomer. The retention
times of the major and minor enantiomers of 13b were 34.9 and 31.0
min, respectively, when 95:5 hexane-2-propanol was used as the eluent.
The enantiomeric ratio was 98:2: mp 86-88 °C; [R]20D ) -74 (c 1.19
1
CH2Cl2); H NMR (CDCl3) δ 7.88 (d, 1H, J ) 7.3 Hz), 7.52 (d, 1H,
J ) 7.3 Hz), 7.47-7.37 (m, 6H), 7.33 (t, 1H, J ) 7.3 Hz), 7.04 (d,
1H, J ) 10.7 Hz), 6.09 (d, 1H, J ) 10.7 Hz), 4.30-4.25 (m, 2H), 2.71
(quint, 1H, J ) 7.3 Hz), 2.62 (quint, 1H, J ) 7.3 Hz), 1.69 (d, 1H, J
) 12.7 Hz), 1.43 (q, 1H, J ) 12.7 Hz), 1.22 (d, 3H, J ) 7.3 Hz), 1.21
(d, 3H, J ) 6.4 Hz), 0.67 (t, 3H, J ) 7.3 Hz); 13C NMR (CDCl3) δ
152.1, 151.8, 139.0, 134.3, 131.2, 130.0, 129.3, 128.9, 128.8, 127.9,
127.5, 126.9, 125.6, 124.7, 91.9, 66.8, 66.3, 65.2, 40.4, 31.4, 22.3, 22.3,
8.7; IR (film) 3200, 3000, 1700, 1600, 1500, 1420, 1150 cm-1; MS
(EI) m/z (relative intensity, %) 433 (0.6, M+), 258 (26, M - PTAD+),
172 (100), 157 (94).
13c. A similar procedure to that used for the electrophilic addition
using 4c (45 mg, 0.17 mmol) and PATD (50 mg, 0.29 mmol, 1.7 equiv)
gave 13c (69 mg, 93% yield) as a single diastereomer. The retention
times of the major and minor enantiomers of 13c were 38.5 and 32.6
min, respectively, when 95:5 hexane-2-propanol was used as the eluent.
1
1
The enantiomeric ratio was 95:5: mp 104-106 °C; [R]20 ) +45 (c
D
1
1.07 CH2Cl2); H NMR (CDCl3) δ 7.83 (d, 1H, J ) 6.4 Hz), 7.63 (d,
1H, J ) 6.4 Hz), 7.48-7.29 (m, 7H), 7.06 (d, 1H, J ) 10.8 Hz), 6.10
(d, 1H, J ) 10.8 Hz), 4.24-4.21 (m, 2H), 3.42 (qq, 1H, J ) 6.8, 6.4
Hz), 1.63 (d, 1H, J ) 12.7 Hz), 1.40 (q, 1H, J ) 12.7 Hz), 1.18 (d,
3H, J ) 5.9 Hz), 1.14 (d, 3H, J ) 4.4 Hz), 1.13 (d, 3H, J ) 6.4 Hz),
0.69 (d, 3H, J ) 6.8 Hz); 13C NMR (CDCl3) δ 152.0, 151.0, 138.3,
135.7, 131.2, 129.0, 128.4, 127.7, 127.5, 127.5, 127.2, 126.9, 125.4,
123.9, 91.6, 67.6, 66.5, 66.0, 40.3, 34.2, 22.2, 18.2, 17.6; IR (film)
3200, 3000, 1700, 1600, 1420, 1120 cm-1; MS (EI) m/z (relative
intensity, %) 447 (0.3, M+), 272 (23, M - PTAD+), 186 (61), 171
(100).
Hydrolysis of 14 to Give Enone 18. The procedure for the
hydrolysis of 13a was applied to 14 (90% de, 83 mg, 0.20 mmol) to
13d. A similar procedure to that used for the electrophilic addition
using 4d (15 mg, 0.049 mmol) and PATD (28 mg, 0.16 mmol, 3.3
equiv) gave 13d (22 mg, 94% yield) as a single diastereomer. The
retention times of the major and minor enantiomers of 13d were 25.9
and 21.4 min, respectively, when 80:20 hexane-2-propanol was used
give 18 (45 mg, 66% yield) having [R]20 ) -145 (c 0.90 CH2Cl2).
D
The optical rotation of 18 agrees with that calculated from the
diastereomeric ratio of 14.
as the eluent. The enantiomeric ratio was 95:5: mp 105-106 °C; [R]20
Electrophilic Addition of PTAD to 6 To Give 15. A sample of
PTAD (150 mg, 0.86 mmol, 1.2 equiv) was added to a solution of 6
(166 mg, 0.72 mmol) in CH2Cl2 (4 mL). After stirring at room
temperature for 2 h, the solution was concentrated in vacuo. The residue
was purified by chromatography (SiO2, eluent 75% EtOAc in hexane)
to give 15 (248 mg, 85% yield). No products other than 15-Si-syn and
15-Si-anti were detected in the NMR spectrum of the isolated sample.
The diastereomeric ratio of 15 was determined by measurement of peak
D
) -69 (c 2.5 CH2Cl2); 1H NMR (CDCl3) δ 7.86 (d, 1H, J ) 7.8 Hz),
7.43 (d, 1H, J ) 8.3 Hz), 7.39-7.18 (m, 12H), 7.01 (d, 1H, J ) 10.4
Hz), 6.46 (d, 1H, J ) 10.4 Hz), 4.29-4.23 (dqd, 1H, J ) 12.7, 5.8,
2.4 Hz), 4.23-4.16 (dqd, 1H, J ) 12.7, 5.8, 2.4 Hz), 1.63 (dt, 1H, J
) 12.7, 2.4 Hz), 1.38 (q, 1H, J ) 12.7 Hz), 1.18 (s, 3H), 1.12 (s, 3H);
13C NMR (CDCl3) δ 152.5, 152.4, 140.6, 138.2, 135.2, 131.1, 130.1,
128.9, 128.8, 128.5, 128.0, 127.7, 127.1, 126.9, 126.6, 126.0, 126.0,
125.3, 92.2, 66.8, 66.5, 66.4, 40.4, 22.3; IR (film) 3200, 1720, 1600,
1420, 1110, 700 cm-1; MS (EI) m/z (relative intensity, %) 481 (0.1,
M+), 306 (17, M - PTAD+), 220 (100).
1
areas for the olefinic protons in the 6.2 ppm region of the H NMR
1
spectrum as 72:28. The H NMR spectrum of the minor diastereomer
15-Si-anti was the same as that of the major product (14-Si-syn) from
5. The diastereomeric mixture of 15 (15-Si-syn:15-Si-anti ) 72:28)
13e. A similar procedure to that used for the electrophilic addition
using 4e (86 mg, 0.37 mmol) and PATD (80 mg, 0.46 mmol, 1.2 equiv)
in CH2Cl2 (3 mL) for 30 min gave 13e (108 mg, 71% yield) as a single
diastereomer. The retention times of the major and minor enantiomers
of 13e were 28.9 and 24.6 min when 85:15 hexane-2-propanol was
used as the eluent. The enantiomeric ratio was 91:9: [R]20D ) -56 (c
had an optical rotation of [R]20 ) -65 (c 0.80 CH2Cl2). 15-Si-syn:
D
1H NMR (CDCl3) δ 7.88 (d, 1H, J ) 7.8 Hz), 7.56-7.32 (m, 8H),
6.98 (d, 1H, J ) 10.5 Hz), 6.21 (d, 1H, J ) 10.5 Hz), 4.36-4.28 (m,
1H), 4.24-4.16 (m, 1H), 3.96 (dd, 1H, J ) 11.7, 3.9 Hz), 2.05 (s,
3H), 1.89 (qd, 1H, J ) 12.7, 5.4 Hz), 1.63-1.60 (m, 1H), 1.24 (d, 3H,
J ) 6.4 Hz); 13C NMR (CDCl3) δ 152.5, 151.9, 137.3, 136.5, 131.9,
131.1, 129.5, 128.9, 128.8, 128.0, 127.3, 125.6, 124.7, 124.6, 91.5,
66.8, 61.0, 32.9, 27.9, 22.4; IR (film) 3400, 3000, 1770, 1700, 1600,
1500, 1430, 1300, 1220, 1160, 1080, 750, 660 cm-1; MS (EI) m/z
(relative intensity, %) 230 (18, M - PTAD+), 158 (100).
1
0.56 CH2Cl2); H NMR (CDCl3) δ 8.27 (d, 1H, J ) 8.3 Hz), 7.89-
7.32 (m, 8H), 7.11 (d, 1H, J ) 10.3 Hz), 6.22 (dd, 1H, J ) 10.7, 4.9
Hz), 5.94(d, 1H, J ) 4.9), 4.35 (dqd, 1H, J ) 11.7, 5.9, 2.4 Hz), 4.25
(dqd, 1H, J ) 11.7, 5.9, 2.4 Hz), 1.71(dt, 1H, J ) 11.7, 2.4 Hz), 1.46
(q, 1H, J ) 11.7 Hz), 1.29 (d, 3H, J ) 5.9 Hz), 1.23 (d, 3H, J ) 5.9
Hz); 13C NMR (CDCl3) δ 151.7, 151.1, 139.4, 131.3, 131.2, 130.6,
129.2, 129.1, 128.9, 127.9, 127.4, 126.4, 126.1, 125.3, 92.3, 67.7, 66.4,
51.1, 40.1, 22.1; IR (KBr) 3460, 1770, 1706, 1503, 1420, 1108, 1044,
766 cm-1; MS (EI) m/z (relative intensity, %) 405 (41, M+), 319 (100);
HRMS (EI) calcd for C23H23O4N3 (M) 405.1689, found 405.1653.
Hydrolysis of 13a To Give Enone 18. To a solution of 13a (72
mg, 0.17 mmol) in CH2Cl2 (3 mL) was added 2 M aqueous HCl (2
µL). After 2 h of reaction at room temperature, the solvent was
Time-Course Monitoring of Electrophilic Addition of PTAD to
6. A solution of 6 (19 mM) and PTAD (135 mM) in CDCl3 was
prepared by mixing, and the reaction was immediately monitored by
1H NMR at 293 K in the dark. Formation of three adducts 15-Si-syn
15-Si-anti, and 19 was observed with the decrease of substrate 6. The
signals due to 15-Si-syn and 15-Si-anti agree with the assigned signals
from the isolated adducts. No signals other than those due to the three
adducts and the substrate 6 were detected. The composition of the

Asymmetric Addition of Electrophile to Naphthalenes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2957
reaction mixture was determined by comparison of the peak areas for
the olefinic protons of the three adducts in the 6.2 ppm region and the
aromatic proton of 6 at 6.72 ppm. The time-course of the reaction is
shown in Figure 6. 19: 1H NMR (CDCl3) δ 8.2-7.0 (m, 9H), 6.35 (d,
1H, J ) 10.2 Hz), 6.15 (d, 1H, J ) 10.2 Hz), 4.46-3.94 (m, 3H), 2.03
(s, 3H), 1.95-1.55 (m, 2H), 1.21 (d, 3H, J ) 5.9 Hz).
Hydrolysis of 15 To Give Enone 18. Hydrolysis of 15 (48% de,
120 mg, 0.29 mmol) by the same procedure as that for 13a gave 18
(92 mg, 96% yield) having [R]20D ) -84 (c 0.92 CH2Cl2). The optical
rotation of 18 agrees with that calculated from the diastereomeric ratio
of 15.
(t, 1H, J ) 7.9 Hz), 7.62 (d, 1H, J ) 7.9 Hz), 7.51 (t, 2H, J ) 6.9 Hz),
7.42-7.09 (m, 5H), 5.18 (d, 1H, J ) 2.4 Hz, 6-H), 5.08 (d, 1H, J )
Electrophilic Addition of PTAD to 7 To Give 16. A solution of 7
(46 mM) and PTAD (78 mM) in CDCl3 was prepared in an NMR tube,
2.4 Hz, 5-H), 4.28 (dqd, 1H, J2,3ax ) 10.8 Hz, J1,2 ) 6.4 Hz, J2,3eq
2.4 Hz, 2-H), 4.13 (ddd, 1H, J3ax,4ax ) 11.8 Hz, J4ax,4eq ) 10.2 Hz,
J3eq,4ax ) 2.0 Hz, 4ax-H), 3.99 (ddd, 1H, J4ax,4eq ) 10.2 Hz, J3eq,4eq
)
1
and the reaction was immediately monitored by H NMR at 293 K in
the dark. After 74 min, 84% conversion of 7 to 16 was observed. The
conversion and diastereomeric ratio were calculated by the peak areas
at 6.80 ppm for 7 and those at 6.13 and 6.18 ppm for 16. The major
diastereomer of 16: 1H NMR (CDCl3) δ 7.83-7.81 (m, 1H), 7.71-
7.68 (m, 1H), 7.55-7.30 (m, 7H), 6.56 (d, 1H, J ) 10.2 Hz), 6.13 (d,
1H, J ) 10.2 Hz), 4.38-4.29 (m, 1H), 4.25-4.16 (m, 1H), 2.16 (s,
3H), 1.88-1.76 (m, 2H), 1.33 (d, 3H, J ) 6.3 Hz), 1.24 (d, 3H, J )
5.92 Hz). The minor diastereomer of 16: 1H NMR (CDCl3) δ 7.9-7.2
(m, 9H), 6.49 (d, 1H, J ) 10.2 Hz), 6.18 (d, 1H, J ) 10.2 Hz), 4.4-
4.1 (m, 2H), 2.15 (s, 3H), 1.9-1.7 (m, 2H), 1.33-1.30 (m, 3H), 1.24-
1.21 (m, 3H).
)
3.4 Hz, J3ax,4eq ) 2.0 Hz, 4eq-H), 2.39 (s, 3H, 7-H), 1.85 (dddd, 1H,
J3ax,3eq ) 13.2 Hz, J3ax,4ax ) 11.8 Hz, J2,3ax ) 10.8 Hz, J4eq,2ax ) 2.0
Hz, 3ax-H), 1.62 (dddd, 1H, J3ax,3eq ) 13.2 Hz, J 3eq,4eq ) 3.4 Hz, J2,3eq
) 2.4 Hz, J3eq,4ax ) 2.0 Hz, 3eq-H), 1.33 (d, 3H, J1,2 ) 6.4 Hz, 1-H);
13C NMR (CDCl3) δ 148.1, 140.8, 133.2, 132.7, 129.6, 128.4, 127.8,
127.5, 126.7, 126.5, 126.4, 125.6, 97.9, 82.9, 67.5, 67.4, 65.6, 61.1,
32.5, 29.9, 22.4; IR (film) 3400, 3000, 1700, 1400, 1100, 840, 760
cm-1; MS (EI) m/z (relative intensity, %) 187 (26), 149 (49), 79 (100);
HRMS (FAB) calcd for C23H26O6N3 (MH+) 440.4822, found 440.1831.
Kinetic Measurements. The reaction was started by mixing the
naphthalene compound (80-40 mM) and PTAD (8-2 equiv) in CDCl3
in an NMR tube and monitored by 1H NMR at 293 K in the dark. The
composition of products was calculated from the peak area for olefinic
Hydrolysis of 16 To Give Enone 18. A sample of PTAD (23 mg,
0.13 mmol, 1.4 equiv) was added to a solution of 7 (23 mg, 0.094
mmol) in CH2Cl2 (1.5 mL). After stirring at room temperature for 30
min, 2 M HCl aqueous (2 µL) was added to the reaction mixture. After
4 h reaction at room temperature, the solvent was evaporated in vacuo
and the residue was purified by chromatography (SiO2, eluent 75%
1
protons in the 6.2 ppm region of the H NMR. For the reactions of 6,
a large excess of PTAD was employed to overcome the slow reaction.
The curve fitting was carried out by using KaleidaGraph ver. 3.08d
(Synergy Software).
EtOAc in hexane) to give 18 (31 mg, 98% yield): [R]20 ) -145 (c
D
0.62 CH2Cl2).
OsO4 Oxidation of 14 To Give Diol 17. To a solution of racemic
14 (90% de, 60 mg, 0.15 mmol) in pyridine (0.7 mL) was added OsO4
(151 mg, 0.59 mmol). After the mixture was stirred for 4 h at room
temperature, THF (6 mL), H2O (0.18 mL), Florisil (1.2 g), and sodium
hydrogensulfite (0.5 g) were added to the mixture, and stirring was
continued for 39 h. The resulting mixture was purified by column
chromatography (SiO2, eluent CH2Cl2/THF ) 8/1) to give diol 17 (35
mg, 54% yield) as a single diastereomer. The purified diol was analyzed
Acknowledgment. We are very grateful to Dr. Howard
Maskill (Newcastle upon Tyne) for reading the munscript and
invaluable comments.
Supporting Information Available: Detailed spectral data.
This material is available free charge via the Internet at
http://pubs.acs.org.
1
1
by H NMR spectroscopy. The H NMR signals of 17 were assigned
by using decoupling and NOE measurements: 1H NMR (CDCl3) δ 7.94
JA0029477